Heteroaryloxy-beta-carboline derivatives, their preparation and their use as medicinal agents

ABSTRACT

Heteroaryloxy-β-carboline derivatives of general Formula I ##STR1## wherein R 1  is an optionally substituted heteroaryl residue, 
     R 2  is hydrogen, lower alkyl or lower alkoxyalkyl, 
     X is a COOR 3  -group wherein R 3  means H or lower alkyl, or represents a CONR 4  R 5  -group wherein R 4  and R 5  mean respectively hydrogen or lower alkyl, R 4  and R 5  being capable of forming, together with the nitrogen atom, a 5- to 6-membered heterocycle, or means an oxadiazolyl residue of the formula ##STR2##  wherein R 6  means hydrogen, lower alkyl or cycloalkyl, are valuable pharmaceuticals.

BACKGROUND OF THE INVENTION

This invention relates to novel heteroaryloxy-β-carboline derivatives,their preparation and their use as medicinal agents.

SUMMARY OF THE INVENTION

It is an object of the invention to provide new compounds havingpharmacological properties.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been achieved by providing heteroaryloxy-β-carbolinederivatives of Formula I ##STR3## wherein

R¹ is an optionally substituted heteroaryl residue,

R² is hydrogen, lower alkyl or lower alkoxyalkyl,

X is COOR³, --CONR⁴ R⁵ - or oxadiazolyl of the formula ##STR4##

R³ is H or lower alkyl,

R⁴ and R⁵ independently are each H or alkyl, or

R⁴ and R⁵ together form with the connecting nitrogen atom, a 5-6membered heterocycle, and

R⁶ is hydrogen, lower alkyl or cycloalkyl.

The compounds of this invention possess valuable pharmacologicalproperties. They influence, in particular, the central nervous systemand thus are suitable as psychopharmaceuticals.

The substituent OR¹ can occur in the 5-, 6-, 7-, or 8-positionpreferably in the 5- or 6-position of the β-carboline.

The heteroaromatic R¹ group is, for example, 5- or 6-membered and canoptionally be mono- or polysubstituted, the substituent being located inany desired position of the heteroaromatic. Nitrogen-containingaromatics e.g., containing 1-2 N atoms are preferred as 6-membered ringheteroaromatics, for example, pyridine, pyrimidine, pyrazine andpyridazine, etc. Suitable 5-membered ring heteroaromatics includeoxygen-, sulfur- and/or nitrogen-containing aromatics, for example,furan, thiophene, pyrrole, imidazole, etc., e.g., generally containing1-2 such atoms.

Examples of suitable substituents of the heteroaromatic rings includehalogens, such as fluorine, chlorine or bromine, nitro, amino, nitrilo,lower alkyl and lower-alkoxycarbonyl groups. Generally there are 1-3,preferably 1-2, substituents.

The point of attachment of the heteroaryl ring to the O-atom in OR¹ canbe preferably by any C-atom.

Suitable lower alkyl portions throughout include straight chained aswell as branched, saturated residues of C₁ -C₆ carbon atoms. Examplesthat can be cited are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, sec-butyl, a pentyl, a hexyl, etc. C₁ -C₄ alkylresidues are preferred.

C₁₋₃ -alkyls are preferred for the residues R⁴ and R⁵. If R⁴ and R⁵,together with the nitrogen atom, form a heterocycle, then the latter istypically saturated aliphatic and is 5- to 6-membered and can contain anadditional hetero atom, such as sulfur, nitrogen or oxygen, e.g.,morpholine, piperidine, thiomorpholine, piperazine, pyrrolidine,imidazolidine, pyrazolidine, or isothiazolidine, etc.

Suitable cycloalkyl residues R⁶ can contain 3-7 carbon atoms, rings of3-5 carbon atoms being preferred, for example, cyclopropyl,methylcyclopropyl, cyclobutyl, cyclopentyl, etc.

It is known that certain sites in the central nervous system ofvertebrates exhibit high specific affinity for binding 1,4-and1,5-benzodiazepines (Squires, R. F. and Braestrup, C., Nature[London]266: 734 [1977]) These sites are called benzodiazepinereceptors.

The receptor affinity, important for the pharmacological properties ofthe compounds according to the invention, was determined byinvestigating their capacity for displacing radioactively labeledflunitrazepam from benzodiazepine receptors.

The displacement activity of the compounds according to the invention isindicated as IC₅₀ and ED50 which values. The IC₅₀ value indicated theconcentration which effects a 50% displacement of the specific bindingof ³ H-flunitrazepam (1.0 nM, 0° C.) in samples with a total volume of0.55 ml of a suspension of brain membranes, e.g., of rats.

The displacement test is performed as follows:

0.5 ml. of a suspension of untreated rat forebrains in 25 mM KH₂ PO₄,pH=7.1 (5-10 mg tissue/sample) is incubated for 40-60 minutes at 0° C.together with ³ H-diazepam (specific activity 14.4 Ci/mmol, 1.9 nM) or ³H-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). Afterincubation, the suspension is filtered through a porous glass filter,the residue is washed twice with cold buffer solution, and radioactivityis measured in a scintillation counter.

The test is then repeated but so that before addition of theradioactively labeled benzodiazepine a specific amount or an excessamount of the compound, the displacement activity of which is to bedetermined, is added. Then the IC₅₀ value can be calculated on the basisof the values obtained.

The ED₅₀ value represents the dose of a test compound causing areduction of specific binding of flunitrazepam to the benzodiazepinereceptor in a live brain to 50% of the control value.

The in vivo test is performed as follows:

The test compound is injected into groups of mice in varying doses andnormally intraperitoneally. After 15 minutes, ³ H-flunitrazepam isadministered to the mice intravenously. After another 20 minutes, themice are sacrificed, their forebrain is removed, and the radioactivityspecifically bound to the brain membranes is measured by scintillationcounting. The ED₅₀ value is determined from the dose/effect curves.

The novel compounds of general Formula I exhibit valuablepharmacological properties. In particular, they act on the centralnervous system and thus are suitable as psychopharmaceuticals in humanmedicine.

The compounds of this invention display especially anxiolytic andanticonvulsive activities. In order to study the anxiolytic effect, thecompounds were tested in the 4-plate assay according to the method byBoissier et al., Eur. J. Pharmacol. 4:145-150 (1986). The tableindicates the minimum lowest dose (MED) which increases the locomotoractivity of the punished mice after i.p. treatment.

                                      TABLE                                       __________________________________________________________________________     ##STR5##                 IC.sub.50 ng/mlED.sub.50 mg/kgBindingFlunitrazep                             amInhibition of .sup.3 H                                                                    MEDActivityAnxiolytic                  R.sup.1   R.sup.2                                                                             X        in vitro                                                                            in vivo                                                                              mg/kg i.p.                              __________________________________________________________________________     ##STR6## CH.sub.2 OCH.sub.3                                                                  COOi-prop                                                                              0.75  2.7    3.13                                     ##STR7## H                                                                                    ##STR8##                                                                              0.28  2.8    3.13                                    __________________________________________________________________________

The compounds of general Formula I can be utilized especially for thetreatment of anxiety accompanied by depressions, epilepsy, sleepdisturbances, spasticities, and muscle relaxation during anesthesia. Thecompounds according to the invention also show amnestic ormemory-improving properties. As a result they are useful in treatingAlzheimer's disease and memory loss (amnesia) after accidents. Thelatter properties are especially useful in geriatric patients.

The compounds of this invention can be used for the formulation ofpharmaceutical preparations, for example for oral and parenteral use inaccordance with conventional methods of galenic pharmacy.

Suitable auxiliary agents for formulating pharmaceutical preparationsare those physiologically compatible, organic or inorganic excipientsfor enteral and parenteral use which are inert with respect to thecompounds of this invention. Examples of excipients include: water,saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylatedcastor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicicacid, fatty acid mono- and diglycerides, pentaerythritol fatty acidesters, hydroxymethylcellulose, and polyvinylpyrrolidone. Thepharmaceutical preparations can be sterilized and/or combined withauxiliary materials, such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, buffers, and colorants.

Especially suited for parenteral utilization are injection solutions orsuspensions, particularly aqueous solutions of the active compounds inpolyhydroxymethoxylated castor oil.

Particularly suited for oral administration are tablets, dragees orcapsules with talc and/or hydrocarbon vehicles or binders, such as, forexample, lactose, cornstarch or potato starch. Use can also take placein the liquid form, such as, for example, as an elixir to whichoptionally a sweetener has been added.

The compounds of this invention are usually administered in a dosageunit of 0.05-100 mg of active compound in a physiologically compatibleexcipient. The compounds according to the invention are usuallyadministered in a dose of 0.1-300 mg/day, preferably 1-30 mg/day e.g.,as anxiolytics, for example, analogous to the known agent diazepam.

The compounds of this invention can be prepared in accordance withmethods known per se.

For example, the compounds of general Formula I can be prepared byprocesses wherein

(a) an indole of general Formula II ##STR9## wherein R¹ has the meaningsgiven in Formula I is reacted, in the presence of acids, with anazabutadiene of Formula III ##STR10## wherein X is COOR³ - group with R³meaning lower alkyl or an oxadiazolyl residue of the formula ##STR11##with R⁶ having the above-indicated meanings; or

(b) a β-carboline derivative of general Formula IV ##STR12## wherein Xand R² have the meanings given above, is etherified with halogen-R¹,wherein R¹ has the meanings indicated above; or

(c) a compound of Formula V ##STR13## wherein R¹ and R² have themeanings given above, is reacted with a compound of the formula (R⁶ CO)₂O wherein R⁶ has the meanings indicated above, to form a compound ofgeneral Formula I wherein X means ##STR14## with R⁶ having the meaningsgiven above; and then optionally the compounds produced in accordancewith process (a), (b) or (c),

(α) wherein R¹ means O₂ N-heteroaryl, are reduced to H₂ N-heteroarylcompounds and these are, if desired, subsequently converted intoN.tbd.C-heteroaryl compounds, and

(β) where R¹ means halogen heteroaryl, are dehalogenated, and

(γ) wherein X means COOR³ with R³ being lower alkyl, are interesterifiedor saponified, and the thus-obtained compounds wherein R³ means hydrogenare optionally amidated to compounds wherein X means CONR⁴ R⁵ with R⁴and R⁵ having the meanings given above, or are reacted, with anamidoxime of the formula R⁶ --CNH₂ (═NOH) wherein R⁶ has theabove-indicated meanings, to compounds wherein X means ##STR15## with R⁶having the meanings given above.

In accordance with process (a), reaction of the indole derivative ofgeneral Formula II with the azadiene takes place in the presence ofacids at temperatures of between 50° and 200° C. The reaction isperformed, for example, by heating the indole derivative and theazabutadiene of Formula III in an aliphatic carboxylic acid, such asformic acid, acetic acid, propionic acid or trifluoroacetic acid, or inan inorganic medium, such as phosphoric acid, polyphosphoric acid, etc.It is also possible to add inert organic solvents, such as, for example,toluene, ethyl acetate, dioxane, dimethoxyethane, acetonitrile,dichloromethane, etc.

However, the reaction can also be conducted in the presence of catalyticamounts of a mineral acid, such as sulfuric acid, hydrochloric acid,perchloric acid, etc., in one of the previously recited, inert solvents,and is generally completed after 2-10 hours.

Etherification of the β-carboline derivatives of general Formula IV inaccordance with process (b) takes place, for example, by reacting areactive heteroaryl compound in a polar solvent, e.g. dimethylsulfoxide, dimethylformamide, acetonitrile or ethanol, in the presenceof a base at temperatures up to the boiling point of the solvent.Especially suitable as the reactive heteroaryl compounds are thehalogenides, such as chloride, bromide, or iodide, as well as mesylateor tosylate.

The bases employed can be alkali compounds, such as, for example, sodiumor potassium hydroxide, sodium or potassium carbonate, and others,optionally also in the presence of phase transfer catalysts, e.g. crownethers or "Aliquat" 336. The process is advantageously performed underinert gas atmosphere, for example under nitrogen or argon.

Reduction of the nitro group to the amino group can be effected, forexample, catalytically in polar solvents, at room temperature under H₂pressure or under normal pressure. Preferably, palladium on a support,such as carbon or platinum, in finely divided form, is utilized as thecatalyst. Suitable polar solvents for the reduction are: for example,alcohols or ethers, such asmethanol, ethanol, diethyl ether,tetrahydrofuran, or their mixtures, etc.

Introduction of the cyano group takes place, for example, in accordancewith the Sandmeyer reaction by reacting the diazonium salts, formedintermediately from the amino compounds with nitrites, in the presenceof Cu(I) cyanide with alkali cyanides.

Catalytic dehalogenation is performed, for example, with palladium oncarbon (I0%) with the addition of organic bases, such as, for example,triethylamine in alcohol. In order to avoid interesterifications, thealcohol of the ester component is suitably employed as the solvent. Ifinteresterification is desired, then it is possible, for example, tocarry out the reaction with the corresponding alcohol or alkalialcoholate; if desired, titanium tetraisopropylate can be added as thecatalyst in the anhydrous alcohol. Customarily, the interesterificationis performed at temperatures of 60°-120° C. and is ended after 2-6hours.

Introduction of the tert-butyl ester group takes place, for example, byreacting the carboxylic acid with tert-butoxybisdimethylaminomethane. Ingeneral, the reaction is conducted under an inert gas atmosphere, suchas argon or nitrogen and under exclusion of moisture at an elevatedtemperature.

Saponification of the ester group can take place in an acidic oralkaline process; preferably, an alkaline saponification is carried outby heating the ester with dilute aqueous alkali solution, such aspotassium or sodium hydroxide, in a protic solvent, such as, forexample, methanol, ethanol or ethylene glycol, to temperatures up to thereflux temperature of the reaction mixture.

Carboxylic acid amides are obtained, for example, by reaction withamines from the corresponding imidazolides, which latter are producedintermediately from the carboxylic acids and carbonyl- orthionyldiimidazole. The reaction is performed at room temperature indipolar aprotic solvents, such as, for example, dimethylformamide,dimethylacetamide, etc.

For the introduction of the 1,2,4-oxadiazol-5-yl residue, theβ-carboline-carboxylic acid is made to condense, for example, with anamidoxime of the formula

    R.sup.2 --C(═NOH)NH.sub.2

in an inert solvent boiling above 100° C. and inert with respect to thereactants, at the reflux temperature of the reaction mixture. Suitablesolvents for the condensation reaction are, for example, toluene anddimethylformamide. Advantageously, the free β-carboline-3-carboxylicacid is suitably activated prior to the condensation reaction. For thispurpose, the free acid can be converted, for instance, into the mixedanhydride, into the activated ester, or into the chloride. Alsoadvantageous proved to be activation to the imidazolide withimidazole/thionyl chloride or also carbonyldiimidazole in an aproticsolvent, such as dioxane, tetrahydrofuran, dimethylformamide orN-methypyrrolidone, at temperatures of between Oo and 50° C., preferablyat room temperature.

The 1,2,4-oxidiazol-3-yl-β-carboline derivatives are produced, forexample, from the β-carboline-3-carboxylic acids by converting the acidamides, prepared as usual, with agents splitting off water, e.g., areagent from triphenylphosphine/bromine in the presence oftriethylamine, into the corresponding nitriles. These can subsequentlybe reacted with hydroxylamine to the desiredβ-carboline-3-carboxamidoximes. The resultantβ-carboline-3-carboxamidoximes are combined at room temperature with theacid anhydride (R⁶ CO)₂ O and then heated to the boiling temperature.The reaction is finished after 7 hours and working up is conductedaccording to the usual methods.

The starting materials required are all known or readily preparable fromknown starting materials using fully conventional methods. See, forexample, EP-A-54507 and EP-A-110813.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the preceding text and the following examples, all temperature areset forth uncorrected in degrees Celsius and all parts and percentagesare by weight; unless otherwise indicated.

EXAMPLE 1 5-(2-Pyrazinyloxy)-β-carboline-3-carboxylic Acid Ethyl Ester

Under ice cooling, a mixture of 2 ml of glacial acetic acid and 0.3 mlof trifluoroacetic acid is combined with 260 mg of1,4-bis(dimethylamino)-2-azabutadiene3-carboxylic acid ethyl ester andstirred for 10 minutes. Then 211 mg of 4-(2-pyrazinyloxy)indole is addedand the mixture agitated under a nitrogen atmosphere at room temperaturefor 24 hours and subsequently heated for 2 hours under reflux (150°-160°C. bath temperature). After cooling, the mixture is poured into Ksolution, the crystallized product is suctioned off, rinsed with water,and recrystallized from ethanol, thus obtaining 190 mg (56%), mp264°-266° C. (EtOH).

The starting material is obtained as follows:

A solution of 2.66 g of 4-hydroxyindole in 60 ml of DMSO is combinedwith 1.4 g of potassium hydroxide (pulverized) and stirred under an N₂atmosphere for one hour at room temperature. After adding 2.5 g of2-chloropyrazine, the mixture is heated for 2 hours to 100° C., pouredinto water, and extracted with ethyl acetate. The residue from theorganic phase is purified over silica gel, thus obtaining 2.95 g (70%)of 4-(2-pyrazinyloxy)indole, mp 192°-193° C.

EXAMPLE 2 5-(5-Nitro-2-pyridyloxy)-β-carboline-3- carboxylic Acid EthylEster

Melting point 298°-300° C. Analogously to Example 1 from4-(5-nitro-2-pyridyloxy)indole.

The starting material is obtained analogously to Example 1 from4-hydroxyindole and 2-chloro-5-nitropyridine, mp 169°-170° C.

EXAMPLE 3 5-(2-Pyrimidinyloxy)-β-carboline-3-carboxylic Acid Ethyl Ester

Melting point 273°-275° C. Analogously to Example 1 from4-(2-pyrimidinyloxy)indole.

The starting material is produced analogously to Example 1 from4-hdyroxindole and 2-chloropyrimidine, mp 233°-234° C. (diisopropylether).

EXAMPLE 4

3-(3-Ethyl-1,2,4-oxadiazol-5-yl)-5-(2-pyrazinyloxy)-β-carboline

Under ice cooling, a mixture of 4 ml of glacial acetic acid and 0.5 mlof trifluoroacetic acid is combined with 340 mg of1,4-bis(dimethylamino)-3-(3-ethyl-1,2,4-oxadiazolyl-5-yl)-2-azabutadieneand stirred for 10 minutes. Thereafter, 211 mg of4-(2-pyrazinyloxy)indole is added, and the mixture is maintained firstat room temperature for 24 hours, then 2 hours at 100° C., and finallyfor 6 hours under reflux. After processing with K₂ CO₃ solution, theproduct is chromatographed over silica gel, thus obtaining 92 mg (25%),mp 278°-280° C. (EtOH).

The azadiene is obtained as follows:

(A) 3-Ethyl-5-(phthalimidomethyl)-1,2,4-oxadiazole

At 40° C., a suspension of 26.0 g of carbonyldiimidazole in 250 ml ofTHF is added to a solution of 65.7 g of phthalimidoacetic acid in 500 mlof THF (absolute). After about one hour, no release of gas can beobserved any longer. At this point in time, a solution of 28.2 g ofpropionamidoxime in 50 ml of THF is added, and the mixture is stirred atroom temperature for 24 hours. After the precipitate has been filteredoff, the filtrate is concentrated under vacuum and, after addition of500 ml of dry xylene, is heated under reflux for 6 hours on a watertrap. The still hot solution is separated from the oily residue andconcentrated under vacuum. Crystallization from EtOH yields 31.5 g(76.5%, based on carbonyldiimidazole) of oxadiazole having a meltingpoint of 106°-107° C.

(B) 5-Aminomethyl-3-ethyl-1,2,4-oxadiazole

A suspension of 32.2 g of phthalimide in 250 ml of methanol is combinedat room temperature with 4.5 g (140 mmol) of hydrazine, the compoundbeing quickly dissolved. The reaction mixture is refluxed for 3 hours,then the resultant precipitate is suctioned off, rinsed with methanol,and the filtrate is concentrated. After making the residue into a slurrywith diethyl ether, the mixture is again filtered, concentrated, and theoil distilled on a bulb tube, boiling point 90°-100° C., 0.03 torr.Yield: 14.87 g (91.6% of theory); n_(D) ²⁰ =1.4691.

(C)

A mixture of 11.5 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 24 mlof dimethylformamide dimethylacetal is heated to 80° C. for 7 hours;during this process, 10 ml of thus-formed methanol is removed bydistillation. After adding another 12 ml of DMF-acetal, the mixture isrefluxed for 3 hours, then subjected to fractional distillation. Thefraction passing over at 155°-160° C. and 0.03 torr, 1,4-bis(di-methylamino)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-aza1,3-butadiene isobtained in a yield of 72% of theory; n_(D) ²⁰ 1.5908.

EXAMPLE 55-(5-Chloro-2-pyridyloxy)-3-(3-ethyl-1,2,4-oxadiazol-5yl)-β-carboline

Analogously to Example 4 from 4-(5-chloro-2-pyridyloxy)indole, mp259°-260° C. (EtOH).

EXAMPLE 65-(2-Pyrimidinyloxy)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-β-carboline

In analogy to Example 4 from 4-(2-pyrimidinyloxy)indole, mp 254°-256° C.(EtOH).

EXAMPLE 75-(5-Nitro-2-pyridyloxy)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-β-carboline

Analogously to Example 4 from 4-(5-nitro-2-pyridyloxy)indole.

EXAMPLE 8 4-Methoxymethyl-5-(2-pyrazinyloxy)- β-carboline-3-carboxylicAcid Ethyl Ester

A solution of 300 mg of5-hydroxy-4-methoxy-methyl-β-carboline-3-carboxylic acid ethyl ester in3 ml of dry dimethyl sulfoxide is combined with 155 mg of K₂ CO₃ andstirred under nitrogen at room temperature for 30 minutes. After adding0.2 ml of 2-chloropyrazine, the mixture is agitated for 6 hours at 95°C., then poured into 1N acetic acid and extracted with ethyl acetate.Purification over silica gel yields 242 mg (64%), mp 130°-131° C.(diethyl ether).

The starting material is obtained by catalytic hydrogenation (Pd/C/H₂ inEtOH) of the 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acidethyl ester. cl EXAMPLE 9

4-Methoxymethyl-5-(2-pyrimidinyloxy)-β-carboline-3-carboxylic Acid EthylEster

Analogously to Example 8 from 2-chloropyrimidine in acetonitrile, mp96°-98° C. (EtOH).

EXAMPLE 105-(5-Chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic AcidEthyl Ester In analogy to Example 8 from 2-bromo-5-chloropyridine indimethylformamide, mp 156°-158° C. (diisopropyl ether). EXAMPLE 115-(5-Chloro-2-pyridyloxy)-4-methyl-β-carboline-3-carboxylic Acid EthylEster

Analogously to Example 8 from5-hydroxy-4-methyl-β-carboline-2-carboxylic acid ethyl ester and2-bromo-5-chloropyridine in dimethylformamide, mp 194°-196° C. (EtOH).

EXAMPLE 12 6-(5-Nitro-2-pyridyloxy)-β-carboline-carboxylic Acid MethylEster

In analogy to Example 8 from 6-hydroxy-β-carboline-3-carboxylic acidmethyl ester and 2-chloro-5-nitropyridine, mp 150°-155° C.

EXAMPLE 13 4-Methoxymethyl-6-(2-pyrimidinyloxy)-β-carboline-3-carboxylicAcid Ethyl Ester

Analogously to Example 8 from6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester and2-chloropyrimidine, mp 128°-129° C.

EXAMPLE 14 6-(5-Bromo-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic Acid Ethyl Ester

In analogy to Example 8 from6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester with2,5-dibromopyridine, mp 210°-212° C.

EXAMPLE 15 5-(2-Pyrimidinyloxy)-β-carboline-3-carboxylic Acid IsopropylEster

A suspension of 185 mg of 5-(2-pyrimidinyloxy)-βcarboline-3-carboxylicacid ethyl ester in 20 ml of absolute 2-propanol is combined with 0.16ml of titanium isopropylate and refluxed for 90 minutes under an argonatmosphere. After concentration and purification over silica gel, 124 mg(64%) of isopropyl ester is obtained, mp 298°-300° C. (isopropanol).

EXAMPLE 165-(5-Chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic AcidIsopropyl Ester

Analogously to Example 15 from the corresponding ethyl ester, mp190°-191° C. (isopropanol).

EXAMPLE 17 5-(5-Chloro-2-pyridyloxy)-4-methyl-β-carboline-3-carboxylicAcid Isopropyl Ester

Analogously to Example 15 from the corresponding ethyl ester, mp243°-245° C. (isopropanol).

EXAMPLE 18 6-(5-Bromo2-pyridyloxy)-4-methoxymethyl-β-carboline3-carboxylic AcidIsopropyl Ester

In analogy to Example 15 from the corresponding ethyl ester, mp210°-212° C.

EXAMPLE 19 4-Methoxymethyl-6-(2-pyrimidinyloxy)-β-carboline-3-carboxylicAcid Isopropyl Ester

Analogously to Example 15 from the corresponding ethyl ester, mp166°-169° C.

EXAMPLE 20 5-(2-Pyrazinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicAcid

A suspension of 235 mg of4-methoxymethyl-5-(2-pyrazinyloxy)-β-carboline-3-carboxylic acid ethylester in 2.5 ml of 1N sodium hydroxide solution is heated to 110° C. for30 minutes. After cooling, the mixture is adjusted to pH 3 with 2N HCl,the crystallized product is suctioned off and rinsed, yielding 265 mg(88%), mp 236°-237° C.

Analogously there are obtained:

4-methoxymethyl-5-(2-pyrimidinyloxy)-β-carboline-3-carboxylic acid, mp237°-239° C.,

5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-carboxylic acid,mp 226°-227° C.

EXAMPLE 213-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4-methoxymethyl5-(2-pyrazinyloxy)-β-carboline

A solution of 245 mg of4-methoxymethyl-5-(2-pyrazinyloxy)-β-carboline-3-carboxylic acid in 15ml of dimethylformamide is combined with 140 mg ofN,N'-carbonyldiimidazole and stirred for one hour at 50° C. Then 310 mgof propionamidoxime is added and the mixture is stirred for 8 hours atroom temperature, then another 2 hours at 100° C. After concentrationunder vacuum, the residue is combined with 20 ml of xylene and refluxedfor 3 hours. The filtered xylene phase is concentrated and the residuepurified over silica gel, thus obtaining 170 mg (60%), mp 192°-193° C.(ethanol).

Analogously there are obtained:

3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methoxymethyl-5-(2-pyrimidinyloxy)-.beta.-carboline,mp 175°-176° C. (EtOH),5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-3-(3-ethyl1,2,4-oxadiazol-5-yl)-β-carboline,mp 144°-146° C. (diisopropyl ether).

EXAMPLE 225-(5-Chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic AcidIsopropylamide

From the 3-carboxylic acid imidazolide and isopropylamine.

EXAMPLE 23 4-Methoxymethyl-5-(2-pyridyloxy)-β-carboline-3-carboxylicAcid Isopropyl Ester

A suspension of 124 mg of5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester in 15 ml of 2-propanol is combined with 50 mg oftriethylamine and 120 mg of Pd-C (10%) and hydrogenated at roomtemperature and under normal pressure. After absorption of thestoichiometric quantity of hydrogen the mixture is filtered, thefiltrate is concentrated, and the residue is recrystallized from2-propanol, thus obtaining 96 mg (84%), mp 188°-189° C.

EXAMPLE 24 6-(5-Amino-2-pyridyloxy)-β-carboline 3-carboxylic Acid MethylEster

A suspension of 3.65 g of6-(5-nitro-2-pyridyloxy)-β-carboline-3-carboxylic acid methyl ester and0.5 g of Pd-C (10%) in 100 ml of methanol is hydrogenated at roomtemperature and under normal pressure. After absorption of thestoichiometric amount of hydrogen, the mixture is filtered andconcentrated. The residue is crystallized from methanol/diethyl ether,yielding 2.84 g (85%).

EXAMPLE 25 6-(5-Cyano-2-pyridyloxy)-β-carboline-3-carboxylic Acid MethylEster

A suspension of 1.7 g of amino derivative (Example 24) in 10 ml of waterand 2.5 ml of hydrochloric acid (37%) is combined dropwise at -5° C.with a solution of 0.4 g of NaN₂ in 1.5 ml of water, then stirred foranother hour at 0°-5° C. By adding sodium carbonate, solution is thenadjusted to pH 5.5-6 and poured into a mixture, preheated to about 60°C., of 0.5 g of copper (I) cyanide and 1.6 g of potassium cyanide in 10ml of water. After the reaction is completed, the cooled-off solution isextracted with dichloromethane, the organic phase is washed with waterand concentrated. The residue is purified over silica gel, thusobtaining 1.12 g (65%).

EXAMPLE 264-Methoxymethyl-5-(5-nitro-2-thiazolyloxy)-β-carboline-3-carboxylic AcidEthyl Ester

Analogously to Example 8 from 2-bromo-5-nitrothiazole.

EXAMPLE 275-(5-Ethoxycarbonyl-2-furyloxy)-4-methoxy-methyl-β-carboline-3-carboxylicAcid Ethyl Ester

Analogously to Example 8 from 5-bromofuran-2carboxylic acid ethyl ester.

EXAMPLE 285-(5-Formyl-2-thienyloxy)-4-methoxymethyl-β-carboline-3-carboxylic AcidEthyl Ester

In analogy to Example 8 from 5-bromothiophene-2 -carbaldehyde.

EXAMPLE 294-Methoxymethyl-5-(5-nitro-2-thiazolyloxy)-βcarboline-3-carboxylic AcidIsopropyl Ester

Produced analogously to Example 8 from5-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester and2-bromo-5nitrothiazole and subsequent ester interchange analogously toExample 15. mp 190°-192° C. (isopropanol)

EXAMPLE 305-(5-Ethoxycarbonyl-2-furyloxy)-4-methoxymethyl-β-carboline-3-carboxylicAcid Isopropyl Ester

Prepared analogously to Example 29 from 5-bromofuran-2-carboxylic acidethyl ester; mp 191°-192° C. (isopropanol).

EXAMPLE 31 4-Methoxymethyl-5-(2-thiazolyloxy)-β-carboline-3-carboxylicAcid Isopropyl Ester

Produced in analogy to Example 29 from 2-bromothiazole; mp 123°-125° C.(ethyl acetate).

EXAMPLE 326-(5-Bromo-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic Acidtert-Butyl Ester

Produced from the corresponding acid by heating withtert-butoxybis(dimethylamino)methane, mp 173°-175° C.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting form the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A heteroaryloxy-β-carboline of the formula##STR16## wherein R¹ is pyridine, furan, thiophene, pyrrole, imidazoleor thiazole, or one of the above substituted by halo, nitro, amino,cyano, C₁₋₆ -alkyl, or (C₁₋₆ -alkoxy)carbonyl,R² is hydrogen, C₁₋₆-alkyl or C₁₋₆ -alkoxy-C₁₋₆ -alkyl, X is COOR³, CONR⁴ R⁵, or oxadiazoylof the formula ##STR17## R³ is H or C₁₋₆ -alkyl, R⁴ and R⁵ independentlyare each H or C₁₋₆ -alkyl, and R⁵ is hydrogen, C₁₋₆ -alkyl or C₃₋₇-cycloalyl.
 2. A compound of claim 1, wherein R² is C₁₋₆ -alkyl or C₁₋₆-alkoxy-C₁₋₆ -alkyl.
 3. A compound of claim 1 wherein R¹ O is in the 5-or 6- position.
 4. A compound of claim 1 wherein R¹ is pyridine.
 5. Acompound of claim 1 wherein R¹ is furan, thiophene, pyrrole orimidazole.
 6. A compound of claim 1 wherein R¹ is attached to O by aC-atom.
 7. A compound of claim 1 wherein R⁴ and R⁵ are C₁₋₃ -alkyl.
 8. Acompound of claim 1 wherein R⁶ is C₃₋₇ cycloalkyl.
 9. A compound ofclaim 1 wherein R⁶ is H or C₁₋₆ -alkyl.
 10. A compound of claim 1wherein X is COOR³.
 11. A compound of claim 1 wherein X is CONR⁴ R⁵. 12.A compound of claim 1 wherein X is oxadiazolyl. 13.5-(5-nitro-2-pyridyloxy)-β-carbolinc-3-carboxylic acid ethylester,5-(5-chloro-2-pyridyloxy)-3-(3-ethyl-1,2,4-oxadiazolyl-yl)-β-carboline,5-(5-nitro-2-pyridyloxy)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-β-carbolin5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidethyl ester, 5-(5-chloro-2-pyridyloxy)-4-methyl-β-carboline-3-carboxylicacid ethyl ester, 6-(5-nitro-2-pyridyloxy)-β-carboline-3-carboxylic acidmethyl ester,6-(5-bromo-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidethyl ester,5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester,5-(5-chloro-2-pyridyloxy)-4-methyl-β-carboline-3-carboxylic acidisopropyl ester,6-(5-bromo-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester,5-(5-chloro-2-pyridyloxy)-4methoxymethyl-β-carboline-3-carboxylic acid,5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-3-(3-ethyl1,2,4-oxadiazol-5-yl)-.beta.-carboline,5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropylamide, 4-methoxymethyl-5-(2-pyridyloxy)-β-carboline-3carboxylicacid isopropyl ester, 6-(5-amino-2-pyridyloxy)-β-carboline-3-carboxylicacid methyl ester, 6-(5-cyano-2-pyridyloxy)-β-carboline-3-carboxylicacid methyl ester,4-methoxymethyl-5-(5-nitro-2-thiazolyloxy)-β-carboline-3-carboxylic acidethyl ester or,5-(5-ethyxocarbonyl-2-furyloxy)-4-methoxymethyl-β-carboline-3carboxylicacid ethyl ester,each a compound of claim
 1. -
 14. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1 anda pharmaceutically acceptable carrier.
 15. A composition comprising0.05-100 mg of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 16. A method of achieving an anxiolytic effect comprisingadministering a compound of claim
 1. 17. A method of achieving ananticonvulsant effect comprising administering a compound of claim 1.18. A method of claim 16 for treating anxiety accompanied by depression,epilepsy, sleep disturbance or spasticity or for achieving musclerelaxation during anesthesia.